Mutations of myosin XVA in humans and mice cause profound congenital deafness. Myosins are actin based molecular motors that have a conserved head (motor) and neck (light chain binding motifs) and highly divergent tail domains. In collaboration with Dr. Jim Sellers and Dr. Fei Wang at the National Heart Lung and Blood Institute, we are using a baculovirus expression system to purify MYO15A protein consisting of the head and neck domains. The recombinant proteins will be used to study the actin binding, ATP hydrolysis and motility properties of MYO15A. The in vitro motor domain assay will provide us with a means of examining the effect of these mutations on myosin XV motor function. The MYO15A tail contains several domains which are candidates for protein interaction motifs. The identification of proteins that functionally interact with MYO15 may provide the best means of determining the role of MYO15A in the auditory system. In addition, interacting proteins are themselves likely to play crucial roles in hearing and would be strong candidates for proteins encoded by deafness loci. We are therefore using the yeast two hybrid system and phage display to identify proteins that interact with the myosin XVA. Genes that encode poteins that interact with myosin XVA from these two screens will be further examined for biological relevance. In addition, using confocal microscopy, we are transfecting wild type and mutated forms of GFP-Myo15a and other unconventional myosins contructs into organ of Corti explant cultures in order to study in vivo targeting and tethering of mysoin XVa at the tips of stereocilia. We demonstrated that whirlin is cargo of myosin XVa and is transported to the tips of stereocilia by myosin XVA. Both of these proteins are necessary for elonagtion and staircase formation of the stereocilia bundle (Belyantseva et al. 2005).
| Faridi, R; Rehman, A U; Morell, R J et al. (2017) Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet 91:328-332 |
| Mauriac, Stephanie A; Hien, Yeri E; Bird, Jonathan E et al. (2017) Defective Gpsm2/G?i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome. Nat Commun 8:14907 |
| Isgrig, Kevin; Shteamer, Jack W; Belyantseva, Inna A et al. (2017) Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome. Mol Ther 25:780-791 |
| Rehman, Atteeq U; Bird, Jonathan E; Faridi, Rabia et al. (2016) Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness. Hum Mutat 37:991-1003 |
| Fang, Qing; Indzhykulian, Artur A; Mustapha, Mirna et al. (2015) The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing. Elife 4: |
| Lee, Sue I; Conrad, Travis; Jones, Sherri M et al. (2013) A null mutation of mouse Kcna10 causes significant vestibular and mild hearing dysfunction. Hear Res 300:1-9 |
| Stepanyan, Ruben S; Indzhykulian, Artur A; Vélez-Ortega, A Catalina et al. (2011) TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells. J Assoc Res Otolaryngol 12:729-40 |
| Odeh, Hana; Hunker, Kristina L; Belyantseva, Inna A et al. (2010) Mutations in Grxcr1 are the basis for inner ear dysfunction in the pirouette mouse. Am J Hum Genet 86:148-60 |
| Peng, Anthony W; Belyantseva, Inna A; Hsu, Patrick D et al. (2009) Twinfilin 2 regulates actin filament lengths in cochlear stereocilia. J Neurosci 29:15083-8 |
| Belyantseva, Inna A; Perrin, Benjamin J; Sonnemann, Kevin J et al. (2009) Gamma-actin is required for cytoskeletal maintenance but not development. Proc Natl Acad Sci U S A 106:9703-8 |
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